Utility of the 2024 Best Practice Recommendations from the EBMT Cellular Therapy and Immunobiology Working Party for Use of Donor Lymphocyte Infusions after Allogeneic Haematopoietic Stem Cell Transplantation

Introduction:

Donor lymphocyte infusions (DLI) are a widely employed strategy to increase the graft-versus-tumor (GvT) effect of allogeneic hematopoietic stem cell transplantation (HSCT) and/or to sustain donor engraftment in case of mixed chimerism but can increase non-relapse mortality (NRM) risk mainly secondary to the induction of graft-versus-host disease (GvHD). In recent recommendations (doi:10.1016/S2352-3026(24)00098-X), the EBMT CTIWP (Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation) proposed the use of T cell doses adapted to the DLI indication (prophylactic, pre-emptive and therapeutic), the donor type and the time of infusion after transplantation.

Methods and Population:

To evaluate the utility of these recommendations on real-world data, we retrospectively analysed a cohort of 162 patients receiving DLI after allogeneic HSCT at our centre between January 2010 and December 2023. Median age at allogeneic HSCT was 51 years (range 15-74). Transplantation indication was AML or MDS in 57% of patients, ALL in 12%, lymphoma or CLL in 13% CML in 7%, and other haematological malignancies in 6%. First dose of DLI was infused in a median time of 214 days (range 60-3753 days) after allogeneic HSCT. No patient received immunosuppressive drugs at time of DLI. Thirty-seven percent of patients had a history of GvHD (acute GvHD, n=60 and/or chronic GvHD, n=8). Median number of DLI infusions was 2 (range 1-7).

Results:

We analysed patients' outcomes considering if the first dose of DLI was administered in accordance or not with the EBMT 2024 recommendations. We observed a significantly improved overall survival (OS) of patients receiving DLI according to the EBMT recommendations (81%, 95%CI 71%-92%) compared to patients receiving different doses (45%, 95%CI 36%-57%; p<0.0001).

Eighteen patients received prophylactic DLI, 12/18 of them (67%) in accordance with EBMT 2024 recommendations and 6/18 (33%) received either lower (2/18) or higher (4/18) doses. Among the 71 patients receiving pre-emptive DLI, the majority (42/71, 59%) was treated according to the EBMT 2024 recommendations, while 29/71 (41%) did not because of higher (20/71) or lower (9/71) doses administered. Finally, regarding the administration of therapeutic DLI, most patients received lower (60/74, 82%) or higher (7/74, 9%) doses compared to the recommended ones and only 7/74 (9%) patients received therapeutic DLI at recommended doses.

We focused our analysis on the subgroup of patients receiving pre-emptive DLI. Among them, 34 patients (48%) received pre-emptive DLI for treatment of measurable residual disease (MRD) and 37 (52%) for mixed chimerism. The 42 patients receiving doses in accordance with the EBMT 2024 recommendations showed a significantly improved OS (87%, 95%CI 77%-98%; p=0.014) and lower NRM (8%, 95%CI 2%-19%; p=0.038), compared to patients receiving different doses (respectively 58%, 95%CI 40%-84% and 26%, 95%CI 10%-45%). Patients receiving pre-emptive DLI at doses higher than the ones recommended by EBMT displayed a higher cumulative incidence of grade 2-4 acute GvHD within 100 days since DLI infusion (35%, 95%CI 15.1%-55.8%) compared to patients receiving DLI doses according to EBMT recommendations (11.9%, 95%CI 4.3%-23.7%; p=0.023). We observed no difference in terms of relapse incidence between the two groups (p=0.51).

Conclusion:

Our data support the utility of the new EBMT 2024 recommendations on DLI administration after allogeneic HSCT and suggest that following these recommendations might improve patient outcome by reducing the mortality related to the toxicity of the treatment. Future studies involving large scale analyses and prospective clinical trials will further optimize the use of DLI to improve patients' outcomes after allogeneic HSCT.

Bernardi:BMS/Celgene: Research Funding; Neovii: Research Funding. Masouridi-Levrat:Beigene: Other: travel and accomodations expenses ; JAZZ Pharmaceuticals: Other: travel and accomodations expenses ; GILEAD: Other: travel and accomodations expenses . Chalandon:MSD: Other: advisory board and travel support, paid to the institution; Novartis: Other: advisory board and travel support, paid to the institution; Incyte: Other: advisory board and travel support, paid to the institution; BMS: Other: advisory board and travel support, paid to the institution; Pfizer: Other: advisory board and travel support, paid to the institution; Abbvie: Other: advisory board and travel support, paid to the institution; Roche: Other: advisory board and travel support, paid to the institution; Jazz: Other: advisory board and travel support, paid to the institution; Gilead: Other: advisory board and travel support, paid to the institution; Amgen: Other: advisory board and travel support, paid to the institution; Astra-Zeneca: Other: advisory board and travel support, paid to the institution; Pierre Fabre: Other: advisory board and travel support, paid to the institution; Sanofi: Other: travel support, paid to the institution; Janssen: Other: travel support, paid to the institution; Takeda: Other: advisory board paid to the institution; Medac: Other: advisory board paid to the institution; Servier: Other: advisory board paid to the institution. Simonetta:Jansseen: Other: travel support; Incyte: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; AstraZeneca: Other: Travel support; Neovi: Other: travel support; novartis: Other: travel support, Research Funding; BMS/Celgene: Consultancy, Research Funding.